Type II diabetes is a syndrome characterized by resistance to insulin and relative insulin deficiency. While some patients can be managed and euglycemia achieved with oral hypoglycemic agents (OHA) alone, others require insulin. However, despite the use of large doses of insulin, the results of insulin therapy alone are frequently unsatisfactory. The addition of an OHA to the treatment regimen of such patients has been suggested as a method of enhancing insulin action and improving glycemic control. OHA's improve glycemic control, at least acutely, through stimulation of endogenous insulin secretion. This endogenous insulin secretion is potentially important in the control of hepatic glucose output. However, previous studies of combination therapy have demonstrated that fasting hyperglycemia can be improved significantly while post-prandial hyperglycemia remains a problem. Lispro, a fast-acting insulin which provides high serum insulin levels with a short duration of action, may lower glucose excursions during and after meals, and in combination with OHA's may further enhance glycemic control. Therefore, it is possible that by reducing the post-prandial burden on endogenous insulin secretory capacity, more insulin may be available and the ability to regulate fasting plasma glucose may be improved. We are completing an evaluation of the effect of pre-meal lispro therapy on the fasting glucose and average level of glucose control of patients with NIDDM who are sulfonylurea failures. Lispro is given with sulfonylurea in one arm of this cross-over study and sulfonylurea alone in the other. If this study is successful, we anticipate the opportunity to investigate the efficacy of lispro in this setting in a larger study of greater duration.